Transforming growth factor-β (TGF□) comprises a family of structurally related multifunctional cytokines. They have a wide variety of biological actions, including cell growth, differentiation, apoptosis, fibrogenesis and angiogenesis. (Massague et al., Cancer Surv. 12, 81-103, (1992), Piek et al., FASEB J. 13, 2105-2124, (1999), Border & Noble N. Engl. J. Med. 331, 1286-1292 (1994); Govinda and Bhoola, Pharmacol. Ther. 98:257-265 (2003); Cusiefen et al., Cornea 19:526-533; Sakimoto et al., Gene Therapy 7:1915-1924 (2000)) TGFβ is typically secreted in a biologically latent form. It is activated through a complex process of proteolytic activation and dissociation of latency protein subunits. (Massague, Annu. Rev. Biochem. 67, 753-791 (1998)).
The mechanism of action of TGFβ is mediated by its binding to receptors known as TGFβ receptors, types I, II and III. Receptors I and II are transmembrane glycoproteins of 55 and 70 kDa shown to be important in signal transduction. The TGFβ ligand binding site for these receptors is extracellular. The mechanism by which the signaling is thought to be achieved is via activation of phosphorylation of transcription factors known as Smads. (Massague & Wotton, EMBO J. 19, 1745-1754 (1999)).
TGFβ has emerged as a key component of the fibrogenic response to wounding and is upregulated during many different types of wound healing in tissues such as the eye, liver, and skin. (Border & Noble, N. Engl. J. Med. 331, 1286-1292 (1994), Connor et al., J. Clin. Invest. 83, 1661-1666 (1989), McCormick et al., J. Immunol. 163, 5693-5699 (1999), Shah et al., J. Cell Sci. 108, 985-1002 (1995)). In the eye, of the three human isoforms (TGFβ1, TGFβ2, and TGFβ3), TGFβ2 is the predominant one. (Lutty et al., Invest. Opthalmol. Vis. Sci. 34, 477-487 (1993), Pasquale et al., Invest. Opthalmol. Vis. Sci. 34, 23-30 (1993)). TGFβs have been implicated in several scarring processes including proliferative vitreoretinopathy, (Kon et al., Invest. Opthalmol. Vis. Sci. 40, 705-712 (1999)), cataract formation, (Hales et al., Invest. Opthalmol. Vis. Sci. 36, 1709-1713 (1989)), corneal opacities, (Chen et al., Invest. Opthalmol. Vis. Sci. 41, 4108-4116 (2000)), and conjunctival wound healing, (Cordeiro, Clin. Sci. 104, 181-187 (2003)) especially that occurring after filtration surgery for a major blinding disease, glaucoma. In addition, TGFβ in conjunction with connective tissue growth factor (CTGF) has an important role in angiogenesis (Abreu et al., Nature Cell Biol. 4:599-604 (2002)). Furthermore, recent studies have shown that TGF may actually be involved in the pathogenesis of primary open angle glaucoma (Inatani et al., Graefes Arch. Clin. Exp. Opthalmol. 239(2):109-13, 2001; Ochiai et al., Jap. J. Opthalmol. 46(3):249-53, 2002; Gattanka et al., Invest. Opthalmol. Vis. Sci. 45(1):153-8, 2004).
In glaucoma filtration surgery, excessive postoperative scarring at the wound site significantly reduces surgical success. (Migdal et al, Ophthalmology 101, 1651-1656 (1994), Addicks et al., Opthalmol. 101, 795-798 (1983)). Although anti-scarring agents such as mitomycin-C and 5-fluorouracil could help prevent postsurgical scarring and improve glaucoma surgical outcome, (Khaw et al., Arch. Opthalmol. 111, 263-267 (1993), Cordeiro et al., Invest. Opthalmol. Vis. Sci. 40, 1975-1982 (1999)) they do so by causing widespread fibroblast cell death and are associated with severe and potentially blinding complications. (Crowston et al. 449-454 (1998), Stamper et al., Am. J. Opthalmol. 114, 544-553 (1992)). In light of the role of TGFβ in the wound repair process, alternative strategies (Codeiro, Prog. Retin. Eye Res. 21, 75-89 (2002)) such as antibodies (Cordeior et al., Invest. Opthalmol. Vis. Sci. 40, 2225-2234 (1999), Mead et al., Invest. Opthalmol. Vis. Sci. 44, 3394-3401 (2003)) to TGFβ and antisense oligonucleotides (Cordeior, et al., Gene Therapy 10, 59-70 (2003)) have been used to block TGFβ action. However these techniques remain inadequate for the treatment of the debilitating scarification that occurs in many glaucoma. For example, use of antisense therapy is poorly effective in treating various disorders because antisense molecules are known to induce an interferon response in the patient. Use of antibody-based therapies are marred by the need to generate specific antibodies against particular epitopes of a given antigen. Thus, there remains a need to identify new methods of intervening in disorders that result from an over-expression or even mere presence of TGFβ type II receptor.